Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis.

Full Abstract

CONTEXT:
Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis.

OBJECTIVE:
To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine.

DESIGN:
Within-subject, randomized, placebo-controlled study.

SETTING:
Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge.

PARTICIPANTS:
Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement.

INTERVENTIONS:
Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview.

MAIN OUTCOME MEASURES:
Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale).

RESULTS:
Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04).

CONCLUSIONS:
These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

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Author information

Author/s: Corlett, Philip R (PR); Honey, Garry D (GD); Aitken, Michael R F (MR); Dickinson, Anthony (A); Shanks, David R (DR); Absalom, Anthony R (AR); Lee, Michael (M); Pomarol-Clotet, Edith (E); Murray, Graham K (GK); McKenna, Peter J (PJ); Robbins, Trevor W (TW); Bullmore, Edward T (ET); Fletcher, Paul C (PC);

Affiliation: Brain Mapping Unit, Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, England.

Grants: (Agency:Wellcome Trust)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't

Journal: Archives of general psychiatry (Arch Gen Psychiatry), published in United States. (Language: eng)

Reference: 2006-Jun; vol 63 (issue 6) : pp 611-21

Dates: Created 2006/06/06; Completed 2006/06/21; Revised 2007/08/13;

PMID: 16754834, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult
Association Learning - drug effects
Brief Psychiatric Rating Scale - statistics & numerical data
Cognition Disorders - chemically induced; physiopathology
Delusions - chemically induced
Disease Susceptibility - psychology
Dose-Response Relationship, Drug
Female
Frontal Lobe - drug effects; physiopathology
Humans

Ketamine - pharmacology
Magnetic Resonance Imaging
Male
Models, Theoretical
Perceptual Disorders - chemically induced
Placebos
Probability
Psychiatric Status Rating Scales - statistics & numerical data
Psychoses, Substance-Induced - etiology; physiopathology; psychology
Psychotic Disorders - etiology; physiopathology

Associated Chemicals: Placebos (0) ; Ketamine (6740-88-1)

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